Thromboprophylaxis for COVID-19-related coagulopathy: what next?

Patients hospitalized with coronavirus disease 2019 (COVID-19) are at high risk for micro- and macrovascular thromboembolic events due to thromboinflammation and the coagulopathy caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).[1,2] Because of its proven anticoagulation effect, coupled with possible antiviral and anti-inflammatory effects, heparin was the first candidate for prevention of adverse events in COVID-19 patients.[2] Yet, a recent meta-analysis of seven clinical trials using low-molecular-weight heparin (LMWH) or unfractionated heparin suggests no difference in all-cause death between the therapeutic-, i.e. escalated, and standard-dose anticoagulation in hospitalized COVID-19 patients without a formal indication for anticoagulation therapy.[3] The escalated dose significantly reduced the rates of pulmonary and other venous thromboembolism, but was associated with a higher bleeding risk.[3] The findings were consistent with regard to the disease severity (critically vs. non-critically ill COVID-19 patients).[3]

It is important to note that the aforementioned meta-analyis[3] did not include the most recent HEP-COVID trial,[4] the first randomized trial using a classic antithrombotic clinical trial design. This trial, similarly to another important report by the REMAP-CAP, ACTIV-4a, and ATTACC Investigators,[5] suggests that therapeutic-dose LMWH reduced the risk of thromboembolism and death in non-critically ill patients. These two well-designed studies strongly suggest the use of escalated anticoagulation in this group of hospitalized patients, particularly with elevated D-dimer levels.

In contrast, current data agree that escalation of heparin dose in critically ill COVID-19 patients requiring intensive care unit treatment provides no benefit,[3,4,6] so the anticoagulation strategy in such patients is uncertain. In addition to coagulopathy, hyperinflammation, and endothelial disruption, mechanisms responsible for the lack of a beneficial effect in critically ill patients may include lung-related mechanisms. First, therapeutic-dose anticoagulation may exacerbate alveolar haemorrhage in patients with severe pulmonary inflammation.[6] Second, the processes of intra-alveolar coagulation that through isolation of pulmonary pathogens may protect the host from disseminated infection and improve survival in COVID-19 are disturbed.[2] Third, heparin may also inhibit lung recovery and increase the risk of progressive lung injury by sequestering growth factors that contribute to lung repair.[7] Still, mechanisms of possible heparin-related interruption of lung-protective and reparative processes are to be further explored.

An important shortcoming of the antithrombotic trials in COVID-19 is that duration of therapy is not explicitly explored in terms of outcomes. Severely ill COVID-19 patients commonly have a more extended hospital stay and receive prolonged anticoagulation treatment. While a prothrombotic state may be expected at the beginning of the COVID-19 disease, in patients whose disease progresses to severe forms a disseminated intravascular coagulopathy (DIC)-like state may develop.[1,3] It has been estimated that the period of 10–12 days from symptom onset could be the point when a procoagulant state and the predominantly beneficial effect of the anticoagulation end and a DIC-like state begins to develop, thereby increasing the risk of bleeding,[3] especially with therapeutic-dose anticoagulation. Aligned with this is a finding of the HEP-COVID trial that the beneficial effect of therapeutic-dose LMWH was mainly observed within the first 14 days of hospitalization.[4] Accordingly, there is a possibility that a switch of the escalated anticoagulation to standard or intermediate dosing at this point could reduce the risk of bleeding, particularly among severely ill and other patients requiring prolonged anticoagulation. This regimen could be tested in future clinical trials in COVID-19 patients with elevated D-dimer levels and without a contraindication for such an approach.

The risk of heparin-associated bleeding is increased with advanced age, illness severity, longer hospital stay, cardiopulmonary resuscitation, and decreased white blood cell and platelet counts.[2] For this reason, such COVID-19 patients should be cautiously recruited in the therapeutic-dose arm, preferably as separate subgroups, and the duration of anticoagulation should be analysed. The presence of antiphospholipid antibodies should be investigated, whereas D-dimer levels, activated partial thromboplastin time, prothrombin time, and platelet count should be regularly monitored. Current evidence suggests that anticoagulants other than heparin or antiplatelet therapy do not provide a beneficial effect,[8,9] but combinations of anticoagulation regimens may be clinically tested. Finally, a better distinction between moderate and severe disease should be made, particularly with regard to lung injury and oxygen requirement. Taking all these factors into consideration in future trials could reveal COVID-19 patient subgroups who will clearly benefit from therapeutic-dose anticoagulation.